Diagnosis of pulmonary arterial hypertension in a patient with systemic sclerosis
Jörg HW Distler, Marius M Hoeper and Oliver Distler* About the authors
Correspondence *Department of Rheumatology, University Hospital Zurich, Gloriastrasse 25, CH-8091 Zurich, Switzerland
Email oliver.distler@usz.ch
Summary
Background A 42-year-old woman with limited cutaneous systemic sclerosis presented with rapid-onset dyspnea on exertion, which had developed over the previous 8 weeks. She had not experienced any dyspnea before this period. Transthoracic Doppler echocardiography performed 6 months before presentation demonstrated an estimated right ventricular systolic pressure of 32 mmHg. Lung function tests also performed at that time revealed a decreased diffusion capacity for carbon monoxide of 54% and normal lung volumes, and high-resolution CT scan of the lungs was normal.
Investigations Physical investigation, CBC, analysis of C-reactive protein and pro-brain natriuretic peptide, transthoracic Doppler echocardiography, six-minute walk test, lung function tests including diffusion capacity for carbon monoxide, right heart catheter, high-resolution CT scan, and ventilation/perfusion scan.
Diagnosis Pulmonary arterial hypertension associated with limited cutaneous systemic sclerosis.
Management Treatment with oral anticoagulation therapy and the endothelin-receptor antagonist bosentan. Monitoring of adverse effects of bosentan therapy was performed using liver function tests.
Keywords:
echocardiography, pro-BNP, pulmonary arterial hypertension, right heart catheterization, systemic sclerosis
The case
A 42-year-old woman was diagnosed with limited cutaneous systemic sclerosis (SSc) three years ago. At the time of diagnosis, she had suffered from Raynaud's phenomenon for six years and recurrent finger-tip ulcers during the last two winter seasons. The patient reported having no other problems, including no dyspnea on exertion. Physical examination demonstrated two small inactive ulcers at the tips of the third and fourth fingers of the left hand, acrosclerosis with a total modified Rodnan skin score of nine, and telangiectasias on the face. Physical examination did not reveal any other pathological findings. Nailfold capillaroscopy demonstrated a reduced capillary density with dilated and giant capillaries, two microhemorrhages and a few avascular areas highly suggestive of SSc. Lung function tests revealed normal lung volumes and a predicted diffusing capacity for carbon monoxide (DLCO) of 54%. High-resolution CT (HRCT) scanning of the lungs did not demonstrate pathologic findings. The right ventricular systolic pressure (RVSP), as estimated by transthoracic Doppler echocardiography (TTE) was 32 mmHg. Laboratory tests showed an antinuclear antibody titer of 1:10000 and presence of anticentromere antibodies, but not anti-topoisomerase I antibodies or other extractable nuclear antigens. Serum level of N-terminal pro-B-type natriuretic peptide (pro-BNP), which was measured at baseline for comparison at later follow-ups, was within normal limits. The patient was prescribed nifedipine and paraffin baths, and advised to avoid exposure to cold.
The patient responded well to this symptomatic treatment. The intensity and frequency of her Raynaud's attacks decreased considerably and she did not develop digital ulcers during the following years. At the first two annual follow-ups no evidence of progression of SSc was observed. The patient's modified Rodnan skin score remained unchanged, lung function tests demonstrated normal lung volumes, and her DLCO was stable. The TTE-estimated RVSPs were 28–33 mmHg, and chest X-rays were normal.
At the third, and most recent, annual follow-up the patient reported experiencing shortness of breath when climbing stairs. She first noted these symptoms eight weeks before the follow-up appointment and dyspnea had progressed since then. She was otherwise well and had noticed no other physical changes. On physical examination, a slightly accentuated pulmonary component of the second heart sound was noticed, but no murmurs were audible. Lung sounds were normal. No peripheral edema, ascites, hepatomegaly, or jugular vein distension were detectable. The patient's body temperature and CBC were within normal ranges, and her C-reactive protein level was not elevated. TTE was performed and revealed an estimated RVSP of 41 mmHg without evidence of left heart disease. Lung function tests demonstrated a further decrease of the DLCO from 54% to 43%, whereas lung volumes remained normal. In addition, pro-BNP level was found to be elevated to threefold higher than normal values. Right heart catheterization was used to confirm the suspected diagnosis of pulmonary arterial hypertension (PAH). The resting mean pulmonary arterial pressure in this patient was 36 mmHg, with a normal pulmonary wedge pressure of 8 mmHg, an increased pulmonary vascular resistance of 509 dynes/sec/cm5, and a cardiac index of 2.2 l/min/m2. After confirming the diagnosis of PAH by using right heart catheterization, interstitial lung disease and thromboembolic disease were excluded by HRCT and ventilation/perfusion scans. The patient was, therefore, classified as having PAH associated with limited cutaneous SSc. A six-minute walk test was performed with a result of 460 meters and a Borg dyspnea index of 3.
The patient's dyspnea progressed rapidly, with symptoms occurring after slight to moderate exercise, and her PAH was classified as New York Heart Association (NYHA) functional class III. Therapy with oral anticoagulation (phenprocoumon, prothrombin time target international normalized ratio 2.0–3.0) and the oral endothelin A and B receptor antagonist bosentan (62.5 mg twice daily for four weeks, followed by a maintenance dose of 125 mg twice daily) was initiated for the treatment of PAH. The patient responded well to the treatment, with an improvement to NYHA class II after four weeks and an increase in the six-minute walking distance from 460 to 520 meters. In addition, pro-BNP levels dropped to within 1.5 fold of the upper normal range. Bosentan therapy was well tolerated and liver function tests remained normal.
Discussion of diagnosis
Challenges and limitations in diagnosing pulmonary arterial hypertension in patients with systemic sclerosis
This case highlights the challenges and limitations of diagnosing PAH in individuals with SSc. PAH is not rare in patients with SSc. The estimated prevalence varies widely according to the method used for diagnosis. Prevalence of pulmonary hypertension has been suggested to be as high as 26.7% in patients with SSc or with mixed connective tissue disease in a community rheumatology practice setting, with pulmonary hypertension defined as RVSP 
40 mmHg by TTE.1 These data, however, must be interpreted with caution because echocardiography has a high rate of false positives, and the diagnosis of PAH requires right heart catheterization. Another study found that 12% of patients with SSc had PAH, as diagnosed by right heart catheterization.2
Unfortunately, clinical symptoms of PAH are unspecific and are late manifestations of the disease.3 As in this case, dyspnea on exertion is often the leading clinical symptom; however, dyspnea indicates that the characteristic vascular remodeling of small and middle sized arteries and arterioles has already developed. In SSc, the differential diagnosis of unspecific signs and symptoms such as dyspnea on exertion, inability to climb stairs, and fatigue is even more challenging when considering other frequent disease manifestations, such as interstitial lung fibrosis and musculoskeletal disorders and deconditioning.
The lack of early clinical symptoms, poor prognosis, rather high prevalence, and availability of effective therapies provide a rationale for the regular screening for PAH in patients with SSc.
Who should be screened? Risk factors for the development of pulmonary arterial hypertension
PAH can occur in all disease stages of SSc, as well as in all disease subsets. Current recommendations, such as the American College of Chest Physicians guidelines,4 suggest that patients with SSc but without obvious symptoms of PAH should be screened by TTE to facilitate early detection and intervention. Screening has become even more important given that treatment with endothelin-receptor antagonists might improve survival in patients with PAH associated with SSc.4, 5
A high clinical awareness and a low threshold for diagnostic tests is recommended for identification of PAH in patients with other connective tissue diseases.3, 6 Certain subgroups of SSc patients, such as patients with limited cutaneous disease and anticentromere antibodies, are at especially high risk of developing PAH, and there is general agreement that these patients need regular monitoring and particular attention.7 Although PAH can develop in all disease stages and can be the presenting symptom of SSc, it most frequently develops at later stages, years after diagnosis.8
Decreasing isolated DLCO is not a specific symptom of PAH;9 however, a case–control study from the Pittsburgh Scleroderma Database identified decreasing DLCO with normal lung volumes as an excellent predictor of subsequent development of PAH,10 which was confirmed in other studies. Right heart catheterization to detect asymptomatic PAH could, therefore, have been considered for our patient at presentation, when an isolated DLCO of <60% was observed, even with a normal echocardiography and in the absence of symptoms.
Many of these established and potential risk factors for PAH were present in our patient. It has to be emphasized that the discussed research findings have a direct implication for the daily clinical care of SSc patients: those patients with minimal to mild skin fibrosis—who are often considered to have a benign form of the disease—need special attention and screening for PAH, in particular if additional risk factors are present.
What are the best screening tests?
Optimum screening tests need to be fast, noninvasive, readily available, cheap, feasible, and fully validated for the disease parameter they are measuring. Such optimum screening tests do not exist for SSc-associated PAH.11 TTE is the best available and most often recommended screening test for PAH because it fulfils many of the requirements listed above; its usefulness is limited by the fact that the estimated RVSP often does not correlate well with the results obtained by right heart catheterization, giving TTE an incidence of false positives of up to 40%. If sufficiently high thresholds, such as an estimated RVSP >45 mmHg, are used, however, the specificity of TTE might be acceptable. In one study, PAH was confirmed in 97% of patients with an estimated RVSP >45 mmHg by right heart catheterization,12 whereas other studies found lower correlations between estimated RVSPs by echocardiography and the findings on right heart catheterization.13
TTE is not a good method of excluding a diagnosis of PAH, in particular in patients with mild or early forms; therefore, patients might sometimes have PAH detectable by right heart catheterization despite normal or borderline values on echocardiography.12 This fact highlights the need for additional screening tests in order to identify early forms of PAH in patients with SSc. Relatively new techniques, such as stress Doppler echocardiography, are promising,14 but have not yet been validated for routine clinical use. Pro-BNP is a biomarker that correlates well with hemodynamic measures and predicts survival in patients with PAH associated with SSc. The specificity and sensitivity of pro-BNP to predict PAH are similar to those of TTE,15 and pro-BNP is often used as a follow-up marker in patients with PAH. A diagnosis of left heart disease needs to be excluded. As outlined above, lung function tests including DLCO can give additional hints for the presence of PAH.
Right heart catheterization and differential diagnosis
In patients with suspected PAH, the diagnosis should be confirmed by direct measurement of pulmonary hemodynamics by the use of right heart catheterization.16 PAH is defined as a resting mean pulmonary arterial pressure of 25 mmHg with a normal capillary wedge pressure of 
15 mmHg, on right heart catheterization.6 The possibility of elevated pulmonary capillary wedge pressures can only be excluded by right heart catheterization in patients with suspected PAH. Right heart catheterization is, therefore, essential for the correct diagnosis of PAH. Patients with increased pulmonary pressures from other conditions, such as interstitial lung disease or chronic thrombembolic disease, are not classified as cases of PAH. These conditions need to be excluded by procedures such as HRCT and ventilation/perfusion lung scanning.
Treatment and management
The natural disease course of PAH in patients with SSc has poor outcomes (Figure 1). A retrospective cohort study found a 1-year survival rate of only 55% in such patients, which was even worse than that in other forms of PAH17 and much worse than that in patients with SSc who did not have lung disease.18
Figure 1 Chest X-rays of a patient with systemic sclerosis and end-stage pulmonary arterial hypertension.
Arrows indicate dilatation of the right atrium (A) and right ventricle (B). Permission obtained from the European League Against Rheumatism ©; the X-rays were originally published in a module on connective tissue diseases for the European League Against Rheumatism online course on rheumatic diseases (www.eular-onlinecourse.org).
Full figure and legend (20K)Figures & Tables indexDownload Power Point slide (92K)A number of specific treatments have become available for patients with PAH, including prostaglandin-derivatives (epoprostenol, treprostinil, beraprost and iloprost), endothelin-receptor antagonists (bosentan, sitaxsentan and ambrisentan), and the phosphodiesterase-type-5 inhibitor sildenafil. These therapies have been shown to improve hemodynamics, exercise capacity and quality of life in open and randomized controlled trials.3, 19 For patients with NYHA functional class III PAH, the available oral treatments (endothelin-receptor antagonists and sildenafil) are the therapeutic agents prescribed most frequently. No order of preference in these drugs could be definitively concluded from published studies. Rational therapeutic decisions must be made on the basis of the individual patient's specific situation, physician clinical judgment, and patient preferences. Treatment with prostaglandin derivates is an option if administration is feasible and the patient is compliant. On the basis of the current level of evidence, intravenous epoprostenol and inhaled iloprost are preferred over intravenous and inhaled treprostinil. Combination therapies can be considered in the case of treatment failure, but such patients should be included in clinical trials and registries. For current evidence-based treatment recommendations please refer to the latest American College of Chest Physicians guidelines.4 It has to be emphasized that many of these recommendations are based on clinical trials in which patients with SSc or other connective tissue diseases were only a subgroup of the study cohort; the majority of patients suffered from idiopathic PAH. Recent data indicate that, compared to historical control treatments, bosentan and sitaxsentan improve survival in patients with PAH associated with SSc.20
Although there is no formal evidence of efficacy in randomized controlled trials, anticoagulation treatment is often used in patients with PAH in order to avoid local thrombosis, since severely disturbed blood flow in small pulmonary vessels, as well as an activated coagulation system, are associated with this disease.
Conclusion
PAH contributes significantly to the morbidity and mortality of patients with SSc. PAH can occur in all disease stages and subsets of SSc, but patients with limited cutaneous SSc or anticentromere antibodies, those of older age, and those with decreasing DLCO (together with normal lung volumes), are at particular risk. Regular screening tests for PAH are warranted in patients with SSc, since clinical symptoms, including dyspnea on exertion, are unspecific and occur late in the course of PAH, and effective therapies are available. The most widely used screening tool is the non-invasive TTE; however, TTE can give false-negative and false-positive results, particularly in patients with borderline RVSP values on echocardiography. Lung function tests including DLCO should, therefore, be used in addition to TTE. In patients with suspected PAH, the diagnosis should be confirmed by right heart catheterization.
References
- Wigley FM et al. (2005) The prevalence of undiagnosed pulmonary arterial hypertension in subjects with connective tissue disease at the secondary health care level of community-based rheumatologists (the UNCOVER study). Arthritis Rheum 52: 2125–2132 | Article | PubMed |
- Mukerjee D et al. (2003) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Ann Rheum Dis 62: 1088–1093 | Article | PubMed | ChemPort |
- Distler O and Pignone A (2006) Pulmonary arterial hypertension and rheumatic diseases—from diagnosis to treatment. Rheumatology (Oxford) 45 (Suppl 4): iv22–iv25 | Article |
- Badesch DB et al. (2007) Medical therapy for pulmonary arterial hypertension: updated ACCP evidence-based clinical practice guidelines. Chest 131: 1917–1928 | Article | PubMed |
- McLaughlin VV (2006) Survival in patients with pulmonary arterial hypertension treated with first-line bosentan. Eur J Clin Invest 36 (Suppl 3): S10–S15 | Article |
- Galie N et al. (2004) Guidelines on diagnosis and treatment of pulmonary arterial hypertension: the Task Force on Diagnosis and Treatment of Pulmonary Arterial Hypertension of the European Society of Cardiology. Eur Heart J 25: 2243–2278 | Article | PubMed | ISI |
- Black C (2005) Pulmonary arterial hypertension: are we doing enough to identify systemic sclerosis patients at high risk of this rare condition? Rheumatology (Oxford) 44: 141–142 | Article | PubMed | ChemPort |
- Chang B et al. (2006) Natural history of mild-moderate pulmonary hypertension and the risk factors for severe pulmonary hypertension in scleroderma. J Rheumatol 33: 269–274 | PubMed | ISI |
- Wells AU et al. (1997) Fibrosing alveolitis in systemic sclerosis: indices of lung function in relation to extent of disease on computed tomography. Arthritis Rheum 40: 1229–1236 | PubMed | ChemPort |
- Steen V and Medsger TA Jr (2003) Predictors of isolated pulmonary hypertension in patients with systemic sclerosis and limited cutaneous involvement. Arthritis Rheum 48: 516–522 | Article | PubMed |
- Distler O et al. (2006) Need for improved outcome measures in pulmonary arterial hypertension related to systemic sclerosis. Rheumatology (Oxford) 45: 1455–1457 | Article | PubMed | ChemPort |
- Mukerjee D et al. (2004) Prevalence and outcome in systemic sclerosis associated pulmonary arterial hypertension: application of a registry approach. Rheumatology (Oxford) 43: 461–466 | Article | PubMed | ChemPort |
- Hachulla E et al. (2005) Early detection of pulmonary arterial hypertension in systemic sclerosis: a French nationwide prospective multicenter study. Arthritis Rheum 52: 3792–3800 | Article | PubMed |
- Alkotob ML et al. (2006) Reduced exercise capacity and stress-induced pulmonary hypertension in patients with scleroderma. Chest 130: 176–181 | Article | PubMed |
- Williams MH et al. (2006) Role of N-terminal brain natriuretic peptide (N-TproBNP) in scleroderma-associated pulmonary arterial hypertension. Eur Heart J 27: 1485–1494 | Article | PubMed | ChemPort |
- Hoeper MM et al. (2006) Complications of right heart catheterization procedures in patients with pulmonary hypertension in experienced centers. J Am Coll Cardiol 48: 2546–2552 | Article | PubMed |
- Kawut SM et al. (2003) Hemodynamics and survival in patients with pulmonary arterial hypertension related to systemic sclerosis. Chest 123: 344–350 | Article | PubMed |
- Koh ET et al. (1996) Pulmonary hypertension in systemic sclerosis: an analysis of 17 patients. Br J Rheumatol 35: 989–993 | Article | PubMed | ChemPort |
- Hoeper MM (2005) Drug treatment of pulmonary arterial hypertension: current and future agents. Drugs 65: 1337–1354 | Article | PubMed | ChemPort |
- Denton CP et al. (2006) Bosentan treatment for pulmonary arterial hypertension related to connective tissue disease: a subgroup analysis of the pivotal clinical trials and their open-label extensions. Ann Rheum Dis 65: 1336–1340 | Article | PubMed | ChemPort |
Competing interests
JHW Distler has received speaking fees and is a consultant for Encysive Pharmaceuticals and Actelion Pharmaceuticals. MM Hoeper has received speaking fees, grant/research support and is a consultant for Encysive Pharmaceuticals, Actelion Pharmaceuticals, GlaxoSmithKline, Pfizer and Bayer-Schering Pharma. O Distler has received speaking fees and is a consultant for Encysive Pharmaceuticals, Actelion Pharmaceuticals, Array Biopharma and Ergonex Pharma.
Contact the journal about this article
Subject areas under which this article appears: Connective tissue diseases | Diagnosis, imaging and screening
